The observation that fractionated X-irradiation (FX) causes a high incidence of leukemia in genetically susceptible mouse strains was first described by Kaplan and collaborators nearly 50 years ago. Kaplan, H. S., 1963, Nat'l. Cancer Inst. Monograph, 207-217. The presence of thymoma cells has been detected in greater than 90% of mice 4 months after FX-treatment. Muto, M., et al., 1987, Cancer Res. 47:3469-3472. The high incidence and fast onset of FX-induced leukemia suggests the involvement of epigenetic mechanisms in the disease process. Kaplan, H. S., 1963, Nat'l. Cancer Inst. Monograph, 207-217; Becker, Y., et al., 1993, In Vivo 7:281-284; Boniver, J., et al.,1981, Cancer Res. 41:390-392; Defresne, M. P., et al., 1986, J. Nat'l Cancer Inst. 77:1079-1085; Defresne, M. P., et al., 1986, Leukemia Res. 10:783-789; Gjerset, R. A., et al., 1992, Mol. Carcinog. 5:190-198; Haas, M., et al., 1986, EMBO J. 5:1775-1782; Muto, et al., 1985, J. Immunol. 134:2026-2031; Muto, M., et al., 1990, J. Immunol. 144:849-853; Sado, T., et al., 1991, Radiation Res. 32:168-180.
In the past decade, several laboratories have investigated the cellular interactions of FX-induced leukemogenesis. The leukemogenic process induced by FX-treatment can be divided into two stages. Defresne, M. P., et al., 1986, Leukemia Res. 10:783-789. In the first stage, radiation injury causes thymic atrophy and depletion of prothymocytes and other cell populations from the bone marrow. Muto, M., et al., 1987, Cancer Res. 47:3469-3472; Becker, Y., et al., 1993, In Vivo 7:281-284; Muto, et al., 1985, J. Immunol. 134:2026-2031. Tumor induction by cycles of tissue injury and cell regeneration can explain initial observations that an approximate threshold dose of 200 rad is required, apparently to cause sufficient tissue damage. Defresne, M. P., et al., 1986, J. Nat'l Cancer Inst. 77:1079-1085. Greater tumor incidence occurs when radiation is split among 4 doses spaced several days apart. Kaplan, H. S., 1963, Nat'l. Cancer Inst. Monograph, 207-217. Thymic involvement in the disease process is indicated by observations that thymectomy, before or shortly after FX-treatment, prevents tumor induction and that genetic susceptibility to FX is transmitted with thymus grafts. Id. Tumors developing in untreated thymus grafts, after transplantation into thymectomized FX-treated mice, have been immunogenetically identified as donor-derived indicating that FX-treatment of the host can indirectly cause transformation of untreated donor thymus cells. Id. Noting that syngeneic thymus grafts initially become necrotic before they establish in the recipient, Kaplan suggested that transplantation may mimic FX-damage. He postulated that the manner of tissue damage could be nonspecific and that the circumstances of thymic regeneration would determine the leukemogenic outcome; an untreated thymus transplanted into a FX-treated host develops lymphoma but, when transplanted into an untreated host, the untreated thymus regenerates normally.
Stage 1 lymphomagenesis lasts 1-2 months after FX-treatment during which time prethymoma cells first arise in the thymus from surviving cells. Kaplan, H. S., 1963, Nat'l. Cancer Inst. Monograph, 207-217; Muto, M., et al., 1987, Cancer Res. 47:3469-3472; Boniver, J., et al.,1981, Cancer Res. 41:390-392. Stage 1 can be reversed by transfer of nonirradiated bone marrow cells to FX-treated recipients. Shielding of bone marrow during FX-treatment also abrogates tumor development. Kaplan, H. S., 1963, Nat'l. Cancer Inst. Monograph, 207-217. Bone marrow cells do not prevent induction of prethymoma cells but apparently inhibit their progression by restoring cell populations to the damaged thymus. Muto, M., et al., 1987, Cancer Res. 47:3469-3472; Becker, Y., et al., 1993, In Vivo 7:281-284; Boniver, J., et al.,1981, Cancer Res. 41:390-392; Defresne, M. P., et al., 1986, J. Nat'l Cancer Inst. 77:1079-1085. In the 2nd stage of leukemogenesis, occurring from 2 months post FX-treatment onward, the radiation-induced damage becomes irreversible and prethymoma cells progress to overt tumors; cells from this stage can grow autonomously outside the thymus. Muto, M., et al., 1987, Cancer Res. 47:3469-3472.
The thymic microenvironment plays a role in prethymoma development. Becker, Y., et al., 1993, In Vivo 7:281-284; Defresne, M. P., et al., 1986, J. Nat'l Cancer Inst. 77:1079-1085; Defresne, M. P., et al., 1986, Leukemia Res. 10:783-789. FX-treatment has been shown to affect two thymic cell populations involved with T-cell maturation, dendritic cells and thymus epithelial nurse cells. Id. The diminished supply of healthy prothymocytes and dendritic cells from the bone marrow to the atrophied thymus of FX-treated mice appears to be a key factor for leukemia development. Kaplan, H. S., 1963, Nat'l. Cancer Inst. Monograph, 207-217; Becker, Y., et al., 1993, In Vivo 7:281-284; Boniver, J., et al.,1981, Cancer Res. 41:390-392; Sado, T., et al., 1991, Radiation Res. 32:168-180. It has been shown that although FX-treated bone marrow does contain a small number of T-cell precursors, capable of migration to the thymus and expression of Thy-1 antigen, they are unable to proliferate and differentiate into functional T cells. Muto, et al., 1985, J. Immunol. 134:2026-2031. Impaired thymic regeneration eventually results in differentiation arrest of immature prothymocytes. Kaplan, H. S., 1963, Nat'l. Cancer Inst.
Monograph, 207-217; Boniver, J., et al.,1981, Cancer Res. 41:390-392; Sado, T., et al., 1991, Radiation Res. 32:168-180. FX-induced thymomas represent several early stages of T-cell development as evidenced by cell surface antigens and T-cell receptor gene rearrangements; the ability to detect T-cell receptor gene rearrangements within a thymoma cell population implies a clonal outgrowth of individual prethymoma cells. Gjerset, R. A., et al., 1992, Mol. Carcinog. 5:190-198; Muto, M., et al., 1990, J. Immunol. 144:849-853; Amari, N. M., & Meruelo, D., 1987, Mol. Cell. Biol. 7:4159-4168; Crispe, N., and Bevan, M. J., 1987, J. Exp. Med. 138:2013-2018; Diamond, L. E., et al. 1988, Immunogenetics 28:71-80; Shimizu, T., et al., 1993, Leukemia Res. 17:959-965.
FX-induced injury has been proposed to cause leukemia by altering the balance between the rates of differentiation and pre-T cell renewal in the thymus. Gjerset, R. A., et al., 1992, Mol. Carcinog. 5:190-198. To identify mRNA transcripts associated with FX-induced thymomas a cDNA library was constructed from FX-induced thymoma mRNA and differentially screened in an attempt to isolate biologically significant cDNA transcripts. A novel cDNA clone, FX-induced transcript 1 (FXI-T1), is described. For the purposes of this specification, the term "isolate" means to remove from the cell, free of the majority of the genomic DNA and mRNA normally found in a cell. Increased FXI-T1 mRNA expression appears to be associated with FX-induced thymomas.
The inventors have transmitted to Genbank the mRNA sequence of FXI-T1, which sequence was published on Jun. 29, 1996 and given Genbank accession number U38252.